Takeda Pharmaceutical Co.’s Actos diabetes drug may be kept on the market with new warnings, the European Medicines Agency said after reviewing research showing the drug carried a slightly increased risk of bladder cancer.
The benefits of pioglitazone, the active ingredient in Actos and other diabetes treatments, outweigh its risks in a limited group of patients with type 2 diabetes, the London-based agency’s Committee for Medicinal Products for Human Use said Thursday in a statement on its website.
“These medicines remain a valid treatment option for certain patients with type 2 diabetes,” though there is a small increased risk of bladder cancer, the agency said. The risk can be reduced by “appropriate patient selection and exclusion,” including regular reviews of how well the drug is working for individual patients, the agency said.
The European agency’s backing supports the decision made by the U.S. Food and Drug Administration that Actos wasn’t linked to an overall increased cancer risk in all patients who took it.
Actos had sales of ¥387.9 billion in the last fiscal year, accounting for 27 percent of Takeda’s revenue. That makes it the best-selling product for the Osaka-based company, Asia’s largest drugmaker.
The European agency has been reviewing the possible cancer risk of Actos and other medicines containing pioglitazone since March. France’s drug regulator in June said it would pull Actos from the market, and its counterpart in Germany recommended that the EMA suspend marketing approval for the diabetes medicine throughout the 27-nation European Union. Actos was suspended in Mauritius.
Actos, which faces competition from cheaper, generic versions next year, became the world’s biggest-selling diabetes drug after a 2007 study linked rival pill Avandia, sold by London-based GlaxoSmithKline PLC, to a higher chance of heart risks. The EMA in September suspended sales of Avandia, while the U.S. regulator decided the medicine could continue to be sold with new warnings.
Both pills belong to the same drug class as Rezulin, which was made by Warner-Lambert Co. It was pulled from the market in March 2000 because of risks of liver cancer and sudden death. The Glaxo medicine had revenue of $680 million last year, less than half its peak in annual sales.
Some doctors have already stopped prescribing Actos and other so-called thiazolidinediones, or TZDs, partly because patients are nervous about the risks.
Besides heart risks, the drugs have also been associated with fluid retention, weight gain and bone loss, said Neale Cohen, an endocrinologist at the Baker IDI Heart and Diabetes Institute in Melbourne, Australia.
“I don’t think doctors are going to continue to prescribe TZD-class drugs, and as far as my practice is concerned, I will tell my patients to stop taking Actos,” said Albert Levy, an endocrinologist at Mount Sinai in New York, in an email. Levy has already taken his patients off Avandia, he said.
Deciding how to assess the benefits versus risks of TZDs is key, said David Kendall, the chief scientific officer of the American Diabetes Association. Patients who can’t control their blood sugar are at risk for more serious complications of diabetes, such as blindness and the loss of limbs, Kendall said.
“There’s clearly a benefit in controlling blood sugar,” said Kendall, who wants to see additional data before any decisions are made. “There’s no clear evidence that there’s a substantial numeric risk of bladder cancer.”
A study in France found pioglitazone carried a slightly increased risk of bladder cancer, prompting the country’s regulator to order its withdrawal on June 9. The epidemiological study, conducted by the French health insurer, followed patients taking the medicine between 2006 and 2009.
A five-year analysis from a decade-long company-sponsored study of Takeda’s Actos showed an increased risk of bladder cancer in patients who took the drug for the longest periods of time, and at the highest cumulative doses, the FDA said June 15. The chance of developing bladder cancer in patients on pioglitazone for at least 24 months was 1.4 times the chance in diabetic patients not taking the medication.
The association was strongest among patients taking the highest dose, suggesting there is a link “but the risk is fairly small,” said Jenny Gunton, a diabetes researcher at the Garvan Institute in Sydney, adding that the suggestion of risk would “cause some limits to prescribing pioglitazone.”
The medicine wasn’t linked to an overall increased cancer risk in all patients who took it, the agency said. The FDA had required the study under new guidelines for diabetes drug approvals.
Takeda has said it is working with the FDA to update the drug’s prescribing information.
“It’s an unusual cancer, and so there’s a change in the hazard ratio based on a small number of cases,” said Robert Spanheimer, the vice president of medical and scientific affairs at Takeda, in an interview before the recommendations were released. “Bladder cancer occurs so infrequently that you have to do a 10-year analysis.”
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